AU736846B2 - Moldable bioactive compositions - Google Patents
Moldable bioactive compositions Download PDFInfo
- Publication number
- AU736846B2 AU736846B2 AU83874/98A AU8387498A AU736846B2 AU 736846 B2 AU736846 B2 AU 736846B2 AU 83874/98 A AU83874/98 A AU 83874/98A AU 8387498 A AU8387498 A AU 8387498A AU 736846 B2 AU736846 B2 AU 736846B2
- Authority
- AU
- Australia
- Prior art keywords
- bioactive
- composition
- dextran
- polysaccharide
- glass
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- 239000000203 mixture Substances 0.000 title claims description 66
- 230000000975 bioactive effect Effects 0.000 title claims description 34
- 229920002307 Dextran Polymers 0.000 claims description 66
- 229960002086 dextran Drugs 0.000 claims description 52
- 150000004676 glycans Chemical class 0.000 claims description 39
- 229920001282 polysaccharide Polymers 0.000 claims description 39
- 239000005017 polysaccharide Substances 0.000 claims description 39
- 210000000988 bone and bone Anatomy 0.000 claims description 33
- 239000002245 particle Substances 0.000 claims description 30
- 239000005313 bioactive glass Substances 0.000 claims description 28
- 239000011521 glass Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 210000001519 tissue Anatomy 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 11
- 239000002241 glass-ceramic Substances 0.000 claims description 11
- 239000001506 calcium phosphate Substances 0.000 claims description 10
- 235000011010 calcium phosphates Nutrition 0.000 claims description 10
- 230000008439 repair process Effects 0.000 claims description 10
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 10
- 230000003416 augmentation Effects 0.000 claims description 7
- 239000008367 deionised water Substances 0.000 claims description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 229920002491 Diethylaminoethyl-dextran Polymers 0.000 claims description 5
- -1 dextran sulfate Polymers 0.000 claims description 5
- 229960000633 dextran sulfate Drugs 0.000 claims description 5
- 230000002708 enhancing effect Effects 0.000 claims description 5
- 239000003755 preservative agent Substances 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 235000021317 phosphate Nutrition 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 229910004298 SiO 2 Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003086 colorant Substances 0.000 claims description 3
- 230000011164 ossification Effects 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000002188 osteogenic effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims 2
- 230000001939 inductive effect Effects 0.000 claims 2
- 102000008186 Collagen Human genes 0.000 claims 1
- 108010035532 Collagen Proteins 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims 1
- 229910001634 calcium fluoride Inorganic materials 0.000 claims 1
- 229920001436 collagen Polymers 0.000 claims 1
- 238000004040 coloring Methods 0.000 claims 1
- 239000013029 homogenous suspension Substances 0.000 claims 1
- 230000007547 defect Effects 0.000 description 33
- 239000000463 material Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 16
- 239000005312 bioglass Substances 0.000 description 9
- 239000012530 fluid Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 210000004872 soft tissue Anatomy 0.000 description 6
- NKCVNYJQLIWBHK-UHFFFAOYSA-N carbonodiperoxoic acid Chemical compound OOC(=O)OO NKCVNYJQLIWBHK-UHFFFAOYSA-N 0.000 description 5
- 206010018852 Haematoma Diseases 0.000 description 4
- 239000012620 biological material Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 238000002513 implantation Methods 0.000 description 4
- 230000008595 infiltration Effects 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000004568 cement Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000000399 orthopedic effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052586 apatite Inorganic materials 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 230000008468 bone growth Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 238000011587 new zealand white rabbit Methods 0.000 description 2
- 230000000278 osteoconductive effect Effects 0.000 description 2
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 241000252095 Congridae Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241001546602 Horismenus Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000192130 Leuconostoc mesenteroides Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N Na2O Inorganic materials [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000003462 bioceramic Substances 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000000316 bone substitute Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical class [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Chemical compound CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000002356 laser light scattering Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000004373 mandible Anatomy 0.000 description 1
- 210000002050 maxilla Anatomy 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000005541 medical transmission Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 239000006060 molten glass Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 230000003239 periodontal effect Effects 0.000 description 1
- 239000003058 plasma substitute Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000002278 reconstructive surgery Methods 0.000 description 1
- 238000012079 reconstructive surgical procedure Methods 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000001738 temporomandibular joint Anatomy 0.000 description 1
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 210000000216 zygoma Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C3/00—Glass compositions
- C03C3/04—Glass compositions containing silica
- C03C3/076—Glass compositions containing silica with 40% to 90% silica, by weight
- C03C3/097—Glass compositions containing silica with 40% to 90% silica, by weight containing phosphorus, niobium or tantalum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C4/00—Compositions for glass with special properties
- C03C4/0007—Compositions for glass with special properties for biologically-compatible glass
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
- A61F2002/3006—Properties of materials and coating materials
- A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
Description
MOLDABLE BIOACTIVE COMPOSITIONS FIELD OF THE INVENTION The present invention generally relates to bioactive compositions. More particularly, the present invention relates to bioactive compositions with a polysaccharide carrier.
BACKGROUND OF THE INVENTION The use of natural and synthetic bone grafting materials in reconstructive surgery has been well established. Autogenous bone is typically preferred for the repair of bony defects in a variety of dental and orthopedic clinical procedures. Although it is desirable to use autogenous bone for defect repair, it is often in limited supply and there are problems associated with the surgery to harvest these grafts. Allografts are a popular alternative to autografts for promoting osseous ingrowth. Although there is an abundance S•of these cadaver harvested grafts, allografts have their associated problems, including possible disease transmission, incomplete incorporation and lot to lot variability with o *o e* *o« go• *o0•• WO 99/02107 PCT/US98/14158 respect to its capability to induce osseous in-growth. As a result, synthetic bone grafting materials have become popular for use in these types of procedures.
Many calcium phosphate based ceramics have been developed for use as bone grafting substitutes. Bioactive glasses and glass ceramics are examples of these synthetic bone grafting materials. Bioactive glasses and glass ceramics have been utilized as bone replacement materials in a variety of dental and orthopedic reconstructive surgical techniques. These glasses develop a strong bond with hard tissue due to a series of ion exchange reactions between the implant surface and body fluids that result in the formation of a biologically active calcium phosphate film at the implant tissue interface.
See Hench et al. J. Biomed. Mater. Res., Vol. 5, pp. 117-141 (1971), and Hench et al, J.
Biomed. Mater. Res., Vol. 7, pp. 25-42 (1973). Bioactive glasses also have been shown to form a firm bond with soft tissue. See Wilson, er al, J. Biomed. Mater. Res., Vol. pp. 805-817 (1981); Wilson and Merwin, J. Biomed. Mater. Res.: Applied Biomaterials, Vol. 22, No. A2, pp. 159-177 (1988); and Wilson, Low et al, Biomaterials and Clinical Applications, Ed. By Pizzoferrato et al. Elsevier Science Publishers Amsterdam (1987).
Certain bioactive and biocompatible glasses and glass-ceramics, those described in U.S. Patents,.4,159,358; 4,234,972; 4,103,002; 4,189,325; 24,171,544; 4,775,646; 4,857,046, and 5,074,916 (all incorporated herein by reference), have been shown to develop a unique, strongly adherent, chemical bond with hard tissue (bone).
This is a result of the formation of a biologically active calcium phosphate (hydroxycarbonate apatite) film generated in situ by ion-exchange reactions between the glass or glass-ceramic surface and body fluids. This influence results in a strong fixation WO 99/02107 PCT/US98/14158 of the glass or glass-ceramic to the bone surface.
The particulate form of bioactive glasses has been used in the repair of periodontal defects in humans for several years. The material is usually mixed with sterile saline, or the patient's own blood, which forms a coherent mass and remains workable for several minutes before placement in the defect site. Although this approach works well for smaller defect sites, there is the need for filling larger defects where it is desirable to have a more malleable material that can be easily shaped and placed into the defect site. Such a material should be sufficiently cohesive to prevent the problems of particle migration associated with some particulate grafting materials. This type of moldable grafting material can be used in a variety of reconstructive surgical procedures including orthopedic, maxillofacial and dental applications.
Several approaches to defect repair in these procedures include the use of natural and synthetic constituents to achieve the desired osteoconductive and handling properties described above. These graft materials may be in the form of a paste or putty, which either retains its malleable characteristics after implantation, or hardens in situ, similar to a cement. An example of the use of calcium phosphate based cements as a bone filling material is described in U.S. Patent No. 5,522,893. This patent describes a combination of tetracalcium phosphate and dicalcium phosphate salts that are mixed and react to harden and form a hydroxycarbonate (HCA) apatite after implantation. Although the HCA that forms effectively fills the defect site, the material is not osteoconductive. The material is relatively insoluble in water and non-absorbable, being only partially replaced by natural bone tissue.
U.S. Patent No. 5,263,985 ("the '985 patent") describes an implantable material WO 99/02107 PCTIUS98/14158 for promoting bone growth which has a microporous structure exhibiting an average pore size of at least 30 Angstroms. The porous biomaterial is capable of retaining macromolecules having a molecular weight of at least 15,000 and up to 500,000. The '985 patent further describes the use of dextran beads having controlled pore size to stimulate bone and tissue growth. However, only negatively charged beads displayed an osteoinductive effect.
Dextrans have been used as femoral plugs. See Rodriguez et al., Optimization of the mechanical properties of dextran-based femoral plugs, Congr. Int. Technol. Pharm., h 1989, 4, 376-90 which describes compressed dextran powders for use as femoral bone plugs tested for their resistance to disintegration and for their plasticity as a function of molecular weight (17,200 to 5-40 million). Preliminary in vivo results showed that the plugs were completely absorbed at the end of 2 to 20 days.
Dextrans have also been combined with hydroxyapatite. See Manufacture of artificial bones from powdery hydroxvlapatite and dextran, Nagase. Japan Kokei Tokyo Koho JP 63-189,156 August 4, 1988. Hydroxyapatite is not class A bioactive. This article describes artificial bones and prosthetics prepared by mixing hydroxyapatite and dextran with or without water or saline solution. Saline was added to sterilized dextran and mixed with hydroxylapatite powder. The resulting plastic paste was added to bone's missing parts.
In the past, other carriers such as polymethylmethacrylate, glycol dimethacrylate, and polylactic dimethacyrate have been used as carriers for bioactive implant materials.
However, these materials are not resorbable or degrade very slowly and are typically associated with soft tissue infiltration.
WO 99/02107 PCT/US98/14158 SUMMARY OF THE INVENTION It is an object of the present invention to provide compositions and method for the repair, augmentation, reconfiguration or replacement of hard tissue structures which avoids many of the disadvantages associated with presently employed materials.
The present invention relates to moldable bioactive compositions including (a) bioactive particles of bioactive glass, glass-ceramics, calcium phosphates, calcium apatites, or mixtures thereof: and a biodegradable polysaccharide carrier including a polysaccharide with an average molecular weight of about 200,000 5,000,000.
DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to moldable bioactive and biocompatible compositions with at least bioactive particles and a biodegradable polysaccharide carrier, for example, dextran, dextran sulfate, diethylaminoethyl dextran, or dextran phosphate or mixtures thereof. As the term "moldable" is used herein, it is intended to describe compositions that have sufficient viscosity such that they are not readily injectable into a patient with a standard needle with an opening smaller in diameter than 17 guage.
Moldable compositions in accordance with the invention may also take the form of a paste.
Applicants have discovered that the use ofpolysaccharides with bioactive particles provides a surprisingly good implant material. The polysaccharide component is absorbed over time and the particulate glass remains at the selected anatomic structures WO 99/02107 PCT/US98/14158 and bonds uniformly throughout the particulate surfaces thereof with the tissue (bone) at the anatomic structures to provide anatomic integrity and to enhance osseous ingrowth.
Polysaccharides such as dextrans are particularly well adapted for such use because the rate at which these materials are resorbed is complementary to the formation of HCA.
The benefits of this balance are extensive. For example, when filling bone defects, soft tissue infiltration is ameliorated. Moreover, polysaccharides such as dextrans are particularly well adapted at maintaining even dispersion of the bioactive particles within the dextran such that over compression of the bioactive particles into the defect site preventing fluid diffusion into the particle mass. which may result in an unfavorable biological result, is avoided.
A biodegradable polysaccharide carrier is any polysaccharide capable of resorbing over time when implanted into a patient such as, for example, dextran, dextran sulfate, diethylaminoethyl dextran. or dextran phosphate or mixtures thereof. Biodegradable polysaccharide carriers in accordance with the present invention preferably include a liquid diluent such as deionized water in amounts in a weight of polysaccharide to volume of diluent of about 1:2 up to about 2:1. Lower molecular weight polysaccharides are cleared from the body faster that those of higher molecular weight. This behavior can be advantageous with respect to the present invention: if it desired that the dextran remain in the site for an extended period, dextrans of relatively high molecular weight may be used.
The use of lower molecular weight dextrans have the advantage of a faster dextran absorption rate, resulting in earlier exposure of the bioactive glass particulate for reaction with the surrounding tissues. During the in vivo analysis however (specifically Example below), an unexpected finding was that if one uses a dextran of too low a molecular WO 99/02107 PCT/US98/14158 weight, the dextran prevents clotting, resulting in deleterious hematoma formation. Use of higher molecular weights eliminates the potential complication of hematoma formation.
The term "viscous solution" as used herein means any moldable or semi solid composition, including highly viscous compositions sometimes referred to as "pastes or putties." As used herein, the term "animal" means mammal including a human. Unless specified otherwise the term "patient" means a human patient. The term "pharmaceutically acceptable" as used herein is consistent with the art and means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof. The term "syringe" means any surgical instrument such as a cement gun, which is standard in the industry, with an opening whose diameter is larger than that of a 17 gauge syringe.
The term "anatomic structure" refers to any site or locus composed of hard tissue (bone) and/or soft tissue within the body of an animal. The term "anatomic integrity" refers to the desired size, shape or configuration of a particular anatomic structure after bonding therewith of the particulate glass phase of the composition of the present invention.
Anatomic structures treatable according to the method of the present invention include, but are not limited to maxilla, mandible, temporomandibular joint, chin, zygomatic arch, nose, ear, tooth root canal, tooth pulp caps, dental restoration; and osseous defects in the appendicular and axial skeleton, including long bones, vertebral spaces and around articulating joints.
One embodiment of the present invention is a pharmaceutically acceptable WO 99/02107 PCT/US98/14158 moldable, semi-solid or solid composition capable of being placed by hand or via a surgical syringe into a defect site, comprising a homogenous mixture ofbioactive and biocompatible glass particulate composition having particle size from about 1000 ,m to about 10 /m in a viscous solution of dextrans or of dextran derivatives having an average molecular weight of about 200,000 to about 5,000,000 daltons and optionally, one or more material enhancing agents, including preservatives, colorants, and flow enhancing, thickening or suspension agents. This invention is particularly useful in the repair, replacement, reconfiguration, reconstruction or augmentation of selected tissue (bone) anatomic structures. The ratio of particulate glass to the viscous solution in the suspension is such that the composition has the ability to be moldable and remains in place after placement.
As noted above, in the discussion of the background of this invention, bioactive and biocompatible material, especially ceramic and glass material, are known in the art of medicine as useful in the restoration of bone and soft tissue. This art is discussed extensively in Introduction to Bioceramics, Ed., L.L. Hench and J. Wilson, especially chapter 1, World Scientific, London (1993). Generally, it has been found that bioactive and biocompatible glasses having the following weight percent compositions give satisfactory results when utilized as the particulate glass component of the invention.
WO 99/02107 PCT/US98/14158 Component Mole Percentage SiO 2 40- 86 CaO 15-46 Na,O 0
P
2 0 5 1- 8 CaF, 0-
B
2 0 3 0-10 The bioactive particulate glass used in the present invention may be prepared according to the methods of the art such as taught in U.S. Patent No's.4,159,358; 4,234,972; 4,103,002; 4,189,325; 94,171,544; 4,775,646; 4,857,046, and 5,074,916. For example, the raw materials SiO 2 CaO, NaO and P20s) are mixed in plastic containers on a ball mill for four hours. The mix is then melted in a platinum crucible at 1350 0 C and homogenized for 24 hours. The molten glass is poured into distilled, deionized water to produce a glass frit. The frit is ground in a mortar and pestle and passed through ASTM sieves to produce the required particle size range. The resulting particle size range, using this process, is then confirmed by optical microscopy, scanning electron microscopy, laser light scattering (Coulter LS 100), or other similar direct measurement technique.
The following compositions of bioactive glasses, known by the trademark "Bioglass" licensed to US Biomaterials, One Progress Boulevard, #23, Alachua, Florida, 32615, have been found to yield particularly good results and are, therefore, preferred.
WO 99/02107 PCT/US98/14158 Table 1 Bioglass (Trademark) Bioactive Glass Compositions in Mole Composition SiO2 Na2O CaO POs 45S5 46.1 24.4 26.9 2.6 52S4.6 52.1 21.5 23.8 2.6 55S4.3 55.1 20.1 22.2 2.6 Other bioactive particles that may be used in accordance with the present invention include bioactive particles of glass ceramics, calcium phosphates, and calcium apatites. These bioactive particles are well known to those of ordinary skill in the art.
Dextrans are polysaccharides of D-glucose and are commercially produced by Leuconostoc mesenteroides and L-dextranicum bacteria. Dextrans have been widely used as plasma substitutes and blood extenders and are considered fully biocompatible and are metabolized in the body. Dextrans are available in a wide range of average molecular weights varying from 4,000 to 40,000,000 daltons and vary in rates of resorption in vivo for two to twenty days depending on the molecular weight. The use of dextran derivatives, including but not limited to diethylaminoethyl dextran and dextran sulfate, with bioactive glass is also within the scope of the present invention.
Dextrans and dextran derivatives useful in the present invention have molecular weights in the range of about 200,000 to about 5,000,000 daltons, preferably in the range of about 200,000 to about 1,000,000.
In addition to bioactive glass, polysaccharides and sterilized de-ionized water, the composition of the present invention optionally contain additives used in the pharmaceutical art to improve its performance and extend its shelf life. These additives WO 99/02107 PCT/US98/14158 include, but are not limited to, preservatives, colorants, and flow and suspension enhancing agents.
The compositions of the present invention may be conveniently prepared in one form by dissolving a polysaccharide such as dextran powder in a diluent (preferably sterile and de-ionized) to form a solution of desired viscosity which is suitable for use.
The ratio of dextran to water will vary according to the molecular weight of the dextran but will be in the range of, for example, about one to four parts dextran to one part water by weight. The resultant viscous aqueous dextran then may be mixed with bioactive glass particles in, for example, the ratio of about one part dextran to about one to three parts bioactive glass (by weight) to form a viscous solution or putty which is moldable.
Alternatively, the compositions may be prepared by mixing the polysaccharide and bioactive glass powders directly. The mixed powders would then be mixed with an appropriate amount of sterile water or other appropriate fluid to form the viscous solution of the desired viscosity.
Additionally, the compositions may be prepared by premixing the polysaccharide, bioactive glass and fluid medium to produce a viscous solution, shaping this mixture to a predetermined shape and drying this resultant shape via freeze-drying or other suitable technique to produce a solid preform. This solid preform may then be supplied to the medical practitioner, at which time the preform is rehydrated, shaped as desired, and implanted.
Because the viscosity and, hence moldability, is a function of the ratio of glass to polysaccharide, this ratio will vary according to application and the preference of the medical practitioner. The prepared viscous composition may be marketed in several WO 99/02107 PCT/US98/14158 viscosities. Further, the practitioner can reduce the viscosity of the prepared solution at the time of insertion by the use of additional fluid. This fluid may include, but is not limited to, sterile water, more dextran, or more preferably, the patient's blood to add autologous osteogenic factors The fluid compositions of the present invention may be placed directly into the defect site by hand, or may be injected using a standard or modified medical syringe or other hardware into the site requiring repair or augmentation. The amount of material used is determined by the professional judgment of the medical practitioner treating the patient. After placement, the polysaccharide will begin to degrade and be removed from the site via normal cellular, fluid transport, and enzymatic action. Degradation and removal of will be essentially complete within about two days to three weeks after implantation, with lower molecular weight polysaccharides being removed at a higher rate than higher molecular weight polysaccharides. Upon removal of the polysaccharide component, the bioactive glass component will remain in the graft site. The bioactive glass particles bond to the hard and soft tissues at the site and create a long-lasting augmentation of the tissue. In a hard tissue site, the particles of glass will react and bond to existing bone and induce the formation of new bone, which will infiltrate the site.
The following examples are offered as illustrations of the present invention and are not to be construed as limitations thereof.
EXAMPLE 1 Forty grams of dextran of average molecular weight of about 400,000 to about WO 99/02107 PCT/US98/14158 500,000 daltons was stirred into 50.0 cc of de-ionized water to form a viscous solution.
The dextran water solution was loaded into a mixing syringe and sterilized by heating at 115 0 C for 35 minutes. Five milliliters of the resultant solution was then mixed by hand with 10.0 cc bioactive glass, composition 45s5, having particle size of about 710 ,m to about 90 to form a moldable paste of uniform consistency.
EXAMPLE 2 A moldable solution is prepared as in Example 1 except that benzyl alcohol is added as a preservative at the rate of 0.05% by weight prior to storing under sterile conditions. Handling properties were similar to those noted in Example 1.
EXAMPLE 3 A moldable solution is prepared as in Example 1 except that the composition of the bioactive glass is Bioglass 52s4.6. Handling properties were identical to those noted in Example 1.
EXAMPLE 4 An in vitro evaluation of dextran as a moldable vehicle was accomplished by mixing a series of different molecular weight dextrans (150,000, 464,000 and 2,000,000 daltons, Sigma Scientific, St. Louis, Mo.) and de-ionized water to achieve a desired WO 99/02107 PCT/US98/14158 viscosity. These solutions then were mixed with a desired amount of Bioglass (trademark) 45s5 particles to form a putty. The mixtures were molded by hand and placed in a simulated defect site of 6.0 mm diameter, created in a bovine femur. The mixtures were evaluated with respect to moldability, cohesiveness, and ease of placement at the site.
The following table summarizes the results of the evaluation of the resulting seven dextran/Bioglass® mixtures Table 2 Sample MW Wt. Dextran/ Volume Dextran/ Consistency Dextran Volume DI Volume Glass #1 150,000 6.0 g./5.0 cc 5.0 cc/5.0 cc Sticky, slightly moldable, flows easily. Difficult to place in defect by hand.
#2 150,000 5.0 g./2.5 cc 2.5 cc/5.0 cc Sticky, moldable, retains shape fairly well. Easy to place in defect but flows less easily.
#3 464,000 3.0 g./5.0 cc 2.5 cc/5.0 cc Sticky, moldable, flows readily when placed in defect.
#4 464,000 3.0 g./5.0 cc 2.5 cc/7.5 cc Dry, not readily moldable, does not flow. Does not stick to walls of defect.
464,000 4.0 g./5.0 cc 5.0 cc/10.0 cc Sticky, very moldable, retains shape very well. Easy to place in defect.
#6 2,000,000 2.5 g./5.0 cc 2.5 cc/5.0 cc Slightly sticky, moldable, retains shape fairly well. Easy to place in defect #7 2,000,000 2.5 g./5.0 cc 2.5 cc/7.5 cc Dry, not readily moldable, does not flow. Does not stick to walls of defect.
The results show that Samples #5 and #6 produced mixtures that were easily molded and placed into the test site by hand. The mixtures were cohesive and tacky, tending to stick to the defect walls. These samples were prepared using dextrans of molecular weights of 464,000 dalton (Sample and 2,000,000 dalton (Sample in different concentrations and a bioactive glass content of 67% by volume. Increasing the glass content to 75% as for Samples #4 and #7 produced drier materials. These 14 SUBSTITUTE SHEET (RULE 26) WO 99/02107 PCT/US98/14158 compositions became moldable on the addition of more fluid, in this case a few drops of deionized water being added. Use of the 150,000 dalton dextran (Samples #1 and or lower concentrations of the 464,000 dalton dextran (Sample produced mixtures having a viscosity suitable for injection through a syringe.
Example In an early animal study, eighteen New Zealand White rabbits were implanted with a mixture of 150,000 dalton dextran (3 grams dextran in 5 cc water) and 710pm- 90gm 45s5 bioactive glass particulate in a volume ratio of one part dextran to 3 parts bioactive glass. Six-mm diameter defects were created bilaterally in the distal femurs of the rabbits and filled with the graft mixture. During the procedure, it was noted that the material was difficult to place and did not stay in the defect. Profuse bleeding was noted at the defect sites and two days after surgery, all animals had hematomas and swelling around the defect sites. At ten days, all animals were destroyed due to excessive drainage and pain.
Example 6 Forty New Zealand White rabbits were implanted with a series of graft materials to evaluate the effect of the presence of 464,000 dalton dextran on bone formation in a critical size femoral defect (6mm diameter). This defect is termed critical sized since an unfilled control defect will not heal even after six months. The following graft materials were evaluated: #1 Autogenous bone #2 Particulate Bioglass® #3 Particulate Bioglass® with 500,000 daltons dextran #4 Particulate Bioglass® with Autogenous bone(50:50) #5 Particulate Bioglass® with Autogenous bone(50:50) with 500,000 daltons dextran Samples #3 and #5 were identical to samples #2 and respectively, with the exception of the addition of the dextran solution. This dextran solution (3.0 grams 464,000 daltons dextran to 5.0 grams water) was mixed with 710 m-90gm 45s5 bioactive glass particulate in a volume ratio of one part dextran to three parts bioactive glass. These samples were similar to Sample #4 in Example 4 and were mixed with small quantities of the blood from the surgical site at the time of implantation for easier handling. Six-mm diameter defects were created bilaterally in the distal femurs of the rabbits and manually filled with the graft materials. Eight animals were used for each test material and were left to heal for periods of 1, 2, 3, 6, and 12 weeks. No hematoma formation was noted over the course of the study. At sacrifice, the defect sites were evaluated using radiography, histology, and histomorphometric analysis. The results indicated no differences between the samples containing dextran and those without dextran in terms of cellular reaction or inflammation at one week. At two weeks, the only difference noted was a decrease in ::15 new bone tissue infiltration at two weeks for samples containing dextran (Samples #3 and although this infiltration exceeded 50% for all graft materials. By four weeks, however, bone ingrowth had increased for the all dextran-containing samples such that -ingrowth equaled that from the non-dextran-containing samples, indicating complete absorption of the dextran. That ingrowth equaled that of the autogenous graft sites .*o20 demonstrates that the graft material containing dextran is as effective in filling bone defects as the gold standard of autogenous bone grafting. By comparison, the unfilled controls showed little or no bone ingrowth within this same time.
The term "comprises/comprising" when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
016 16 ujl
Claims (7)
1. A moldable bioactive composition comprising: bioactive particles of bioactive glass, glass-ceramics, calcium phosphates, calcium apatites, or mixtures thereof, and; a biodegradable polysaccharide carrier including a polysaccharide with an average molecular weight of about 200,000 5,000,000.
2. The bioactive composition of claim 1, further comprising a colorant, preservative, flow enhancer, or suspension enhancer, or mixtures thereof.
3. The bioactive composition of claim 1, wherein the polysaccharide carrier includes a diluent.
4. The bioactive composition of claim 3, wherein the diluent is deionized water. The bioactive composition of Claim 1, wherein said particles include particles up to about 1000 m.
6. The bioactive composition of claim 1, wherein said particles include particles between about 90 um to about 710 gm.
7. The composition of Claim 1, wherein said bioactive glass particles comprise the following composition: Component Mole Percentage SiO 2
40- 86 CaO 15-46 NaO 0 WO 99/02107 PCT/US98/14158 P 2 0 5 1 -8 CaF2 0 B 2 0 3 0-10 8. The composition of Claim 1, wherein said polysaccharide is dextran, dextran sulfate, diethylaminoethyl dextran, or dextran phosphate or mixtures thereof. 9. The composition of Claim 5, wherein said polysaccharide has an average molecular weight of about 300,000 2,000,000. 10. The biocompatible pharmaceutical composition of Claim 5, wherein said polysaccharide has an average molecular weight of about 450,000 550,000. 11. The composition of claim 1, with substantially no amount of collagen. 12. The composition of claim 1, wherein the biodegradable polysaccharide carrier and the bioactive particles are present in a volume to volume ratio of about 1:3 to about 3:1. 13. The composition of claim 12, wherein said polysaccharide carrier includes a diluent. 14. The composition of claim 13, wherein said diluent is water. The composition of claim 13, wherein said diluent is present in a diluent to polysaccharide ratio of about 1:3 to 3:1. 16. The composition of claim 1, wherein the biodegradable polysaccharide carrier and the bioactive particles are present in a volume to volume ratio of about 1:2. 17. A moldable bioactive composition for repair, replacement, reconfiguration, reconstruction or augmentation of selected hard tissue anatomic structures in a patient in need thereof comprising bioactive particles of bioactive glass, glass- ceramics, calcium phosphates, calcium apatites, or mixtures thereof and a biodegradable polysaccharide carrier, dextran, dextran sulfate, diethylaminoethyl dextran, or dextran phosphate or mixtures thereof. 18. A method for repair, replacement, reconfiguration, reconstruction or augmentation of selected hard tissue (bone) anatomic structures in a patient in need thereof, comprising repair and/or augmentation of hard tissue (bone) of said patient a homogenous suspension ofbioactive and biocompatible glass particulate composition having particle size from about 710 gm to about 90 /im in an aqueous solution of dextrans or of dextran derivatives having an average molecular weight of about 500,000 daltons and optionally one or more preservative, coloring, flow enhancing, or suspension enhancing agents. 19. A method for inducing osteogenesis comprising contacting a patient in need thereof with an effective osteogenic amount of a mixture of: bioactive particles of bioactive glass, glass-ceramics, calcium phosphates, calcium apatites, or mixtures thereof; a biodegradable polysaccharide carrier including a polysaccharide with an average molecular weight of about 200,000 5,000,000. 20. The method of claim 19, wherein said biodegradable polysaccharide carrier includes a diluent in a polysaccharide to diluent ratio of about 1:3 to 3:1. 21. Use of bioactive particles of bioactive glass, glass-ceramics, calcium phosphates, calcium apatites, or mixtures thereof; and a biodegradable polysaccharide carrier including a polysaccharide with an average molecular weight of about 200,000 5,000,000 in the manufacture of a moldable bioactive composition for inducing osteogenesis. 19 v1_ Ys^ C4
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US6537574B1 (en) | 1992-02-11 | 2003-03-25 | Bioform, Inc. | Soft tissue augmentation material |
US7968110B2 (en) | 1992-02-11 | 2011-06-28 | Merz Aesthetics, Inc. | Tissue augmentation material and method |
US7060287B1 (en) | 1992-02-11 | 2006-06-13 | Bioform Inc. | Tissue augmentation material and method |
TW434006B (en) * | 1999-08-13 | 2001-05-16 | Bioform Inc | Tissue augmentation material and method |
US8876532B2 (en) | 2002-07-31 | 2014-11-04 | Dentsply International Inc. | Bone repair putty |
WO2004011053A1 (en) | 2002-07-31 | 2004-02-05 | Dentsply International Inc. | Bone repair putty comprising porous particulate and carrier gel |
FR2850282B1 (en) * | 2003-01-27 | 2007-04-06 | Jerome Asius | INJECTABLE IMPLANT BASED ON CERAMIC FOR THE FILLING OF WRINKLES, CUTANEOUS DEPRESSIONS AND SCARS, AND ITS PREPARATION |
EA200501421A1 (en) * | 2003-03-04 | 2006-04-28 | Дзе Текнолоджи Девелопмент Компани Лтд. | ORAL COMPOSITION OF INSULIN AND METHODS OF ITS MANUFACTURE AND APPLICATION |
DE102004012411A1 (en) * | 2004-03-13 | 2005-09-29 | Dot Gmbh | Composite materials based on polysilicic acids and process for their preparation |
EP1655042A1 (en) * | 2004-11-02 | 2006-05-10 | Vivoxid Oy | A medical device |
US20070184087A1 (en) | 2006-02-06 | 2007-08-09 | Bioform Medical, Inc. | Polysaccharide compositions for use in tissue augmentation |
EP1872806A1 (en) * | 2006-06-28 | 2008-01-02 | Vivoxid Oy | Implant, its uses and methods for making it |
WO2008000888A2 (en) * | 2006-06-28 | 2008-01-03 | Vivoxid Oy | Implant containing a source of oxygen |
US9113868B2 (en) | 2011-12-15 | 2015-08-25 | Ethicon Endo-Surgery, Inc. | Devices and methods for endoluminal plication |
US9173657B2 (en) | 2011-12-15 | 2015-11-03 | Ethicon Endo-Surgery, Inc. | Devices and methods for endoluminal plication |
US8992547B2 (en) | 2012-03-21 | 2015-03-31 | Ethicon Endo-Surgery, Inc. | Methods and devices for creating tissue plications |
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